Correlation of the combined symptom and medication score with quality of life, symptom severity and symptom control in allergic rhinoconjunctivitis

Abstract Background The European Academy of Allergy and Clinical Immunology recommended the Combined Symptom and Medication Score (CSMS) as primary endpoint in clinical trials on allergen‐specific immunotherapy (AIT) in allergic rhinoconjunctivitis. Here, the correlation between the CSMS and the validated standardised Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)), Rhinitis Control Assessment Test (RCAT) and Visual Analogue Scale (VAS) was analysed. Methods Two prospective, multicentre, non‐interventional studies on tree pollen, grass pollen and house dust mite allergic patients were performed. The first study comprised 167 patients receiving AIT (AIT population), and the second included 56 patients treated with symptomatic medication only (control population). For up to two seasons (pollen)/exposure periods (house dust mites), participants documented their symptoms and medication intake in a CSMS diary, including VAS. In addition, the standardised RQLQ(S) and the RCAT were completed during study visits. Results Comparison between CSMS and RQLQ(S) revealed a positive correlation in the AIT population (r = 0.426) and in the control population (r = 0.569). For CSMS and RCAT, a negative correlation with r = −0.409 (AIT) and r = −0.547 (control) was shown. Positive correlation between CSMS and VAS was also demonstrated with r = 0.585 (AIT) and r = 0.563 (control). Conclusion These results support the assumption that the CSMS correlates with quality of life, symptom severity and symptom control on the one hand, while the moderate strength of correlations on the other hand mirrors distinctions of the CSMS compared to the assessments used here.


| INTRODUCTION
Allergic rhinoconjunctivitis (ARC) is a predominantly eosinophilmediated inflammation of the nasal mucosa and conjunctiva. 1 It is one of the most common allergic disorders, with varying estimates of prevalence and manifestations across different parts of the world. [1][2][3][4][5] The burden of ARC can affect patients' social life and educational or job performance, and is associated with high economic costs. [6][7][8][9][10] Besides allergen avoidance, there are two principal pharmaceutical approaches to treat ARC. First, in conventional pharmacotherapy, antihistamines, antileukotrienes, corticosteroids or monoclonal antibodies are used to reduce or control the symptoms. 11 Secondly, allergen-specific immunotherapy (AIT) is the only disease modifying causal therapy being available aiming to induce long-term tolerance to allergens. [11][12][13] In AIT, allergens are presented to the immune system, either by subcutaneous injection (subcutaneous immunotherapy -SCIT) or sublingually (sublingual immunotherapy -SLIT). 12 Randomised clinical trials assessing AIT in ARC show clinical and methodological heterogeneity on the defined endpoints, making comparisons difficult and to date commonly accepted standards have not been established. [13][14][15] Widely used instruments which have already been proven to reflect the extent of ARC associated impact on the quality of life, symptom control and impairment by symptoms, respectively, include the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), 16,17 the Rhinitis Control Assessment Test (RCAT) [18][19][20] and Visual Analogue Scales (VAS). [21][22][23][24] To standardise the primary outcome in clinical trials for proof of efficacy in AIT and in line with the European Medicines Agency guideline in the development of products for specific immunotherapy, the European Academy of Allergy and Clinical Immunology (EAACI) recommended the Combined Symptom and Medication Score (CSMS). 13,25 The CSMS reflects the sum of daily Symptom Score (dSS) and daily Medication Score (dMS) comprising the rating of 6 symptoms and use of symptomatic medication. 13 In the present study, we performed a comprehensive correlation analysis on CSMS outcomes versus the standardised RQLQ, the RCAT and VAS in order to contribute to the discussions on its applicability as primary endpoint for clinical studies on AIT.

| Study design
We performed two prospective multicentre non-interventional studies based on a common master protocol. The first was an observational study in accordance with Section 4 subsection 23 sentence three of the German Medicinal Product Act, 26 comprising patients ("AIT population") treated with pre-seasonal or perennial subcutaneous AIT with depigmented allergoids. 27 The second was a prospective data acquisition with patients ("control population") taking symptomatic medication only. In up to two observation periods (September 2018-July 2019 and September 2019-July 2020) the participants were requested to complete a CSMS diary, including VAS demonstrating the overall impairment due to ARC symptoms, for at least 30 days during the season (pollen) or exposure period (house dust mites, especially from September to December). In addition, the standardised RQLQ (RQLQ(S); at visits 1-3 and 4-6, if applicable) and the RCAT (at visit 2 and 5, if applicable) were filled in at the study centres. The timing of the visits in relation to the observation period is given in Table 1.

| Ethic compliance
The studies complied with the Declaration of Helsinki and the Good

| Study populations
Eligible patients were adults and children/adolescents aged ≥12 years, suffering from allergies to house dust mites (HDM), tree pollen (TP) or grass pollen (GP) and consequently from rhinitis, conjunctivitis or rhinoconjunctivitis. Individuals with additional allergic asthma were also eligible. In both studies, treatment had already begun, or the decision for therapy had already been made irrespective of study participation. Randomisation, stratification or matching was not performed. The application of AIT and/or symp-

| Assessments
An overview of the observation periods and visits, including the questionnaires used, is shown in Table 1. VASs were applied to assess overall impairment by ARC symptoms (overall VAS), specific impairment by nasal symptoms (nasal VAS) and specific impairment by conjunctival symptoms (conjunctival VAS). Rating was done by marking in a scale between "not impairing" (=0) and "very much impairing" (=100).
The CSMS reflects both symptoms and intake of rescue medication equally weighted daily. The higher the score, the higher the impact of ARC. Table 2 gives a detailed overview of how the CSMS is calculated.

| Data acquisition
The CSMS diary was used for documentation of rhinoconjunctivitis symptoms, symptomatic medication, and impairment by symptoms. It was kept electronically, using the application CSMS+ Diary, including VASs, for mobile devices (Android version 1.022, iOS version 1.1, released by AppCologne GmbH, Cologne, Germany). In 11 cases, the diary was kept on printed forms due to technical reasons. RQLQ(S) and RCAT were filled in on printed forms. During the observation periods, diary data were checked for continuity twice a week. Besides, the diary app reminded the patients of doing their entries daily.
The questionnaires were checked for completeness and plausibility.
By double data entry and reconciliation, data integrity of all paperbased question forms and questionnaires was ensured. The data from CSMS+ Diary was exported and merged with the data from the paper-based question forms. All data were analysed using a patient ID number only. These data were further matched with the information on the pollen season (PS) valid for the respective study location. The start and the end of the PS were defined according to Pfaar et al. 29 PS started at the first of 5 days (out of 7 consecutive days), each with ≥3 (grass) or 10 pollen/m 3 (birch) daily and accounting for a sum of ≥30 (grass) or 100 pollen/m 3 (birch). The end was marked by the last day of series of 5 days, meeting these criteria.
Each study site was assigned to a pollen region as defined by  Germany's National Meteorological Service (DWD). 30 Pollen exposure levels associated to the expected daily mean pollen concentration were classified from 0 (no exposure) to 3 (high exposure) as given by the DWD. The exposure period (EP) for house dust mites was defined as the 30 days with worst incidence of symptoms as documented in the patients' diary.  Table 3 gives an overview of the demographic characteristics, which were comparable between both populations.

| CSMS data acquisition
In total, 20,300 patient diary entries were collected. Of these, 20

| Comparison of seasons/exposure periods within the AIT population with two observations
In TP, mean CSMS slightly decreased, comparing PS 2019-2020.
Mean VAS was similar in both seasons. Mean RQLQ score at the second visit (i.e., peak season) was slightly lower in the second season, while mean RCAT indicated controlled symptoms in both seasons. Surprisingly, in GP, an increase in CSMS, VAS and RQLQ was observed. Consistent with this, the RCAT score decreased, indicating worsened symptom control. In HDM, a decrease in mean CSMS, mean VAS and in mean RQLQ score at peak season was observed (17%, 21% and 15%, respectively). The mean RCAT score increased changing from uncontrolled to controlled symptoms. suggesting that patients enrolled in the control population and not taking AIT therapy had already been remarkably less affected at baseline.

| Correlations between CSMS and validated questionnaires
The

| DISCUSSION
Because of the interdependence of symptoms and medication, the World Allergy Organization (WAO) recommended combined symptom and medication scoring as primary outcome measure. 31 Clark and Schall 32 showed that a combination of the Average Rhinoconjunctivitis Total Symptom Score (ARTSS) and Average Rescue Medication Score (ARMS) provided better discriminatory power than each of them alone.
Grouin et al, 33 suggested a refinement of the RTSS, the Adjusted daily Symptom Score (AdSS), which considers the effect of medication intake on symptom score with a last-observation-carried-forward approach.
A medication score is not added. A comparison between results obtained with a Combined Score (RTSS and RMS) and the AdSS showed that treatment effects were consistently demonstrated with both scores. 34 However, it should be noted that medication scores add important information 33 and contribute to the stepwise approach of medication rating as recommended by the WAO and consider the pharmacologically weighted impact of different medications on the symptom score. 13,31 Symptom and medication scoring can be done daily. 31 Daily assessment is also possible using Visual Analogue Scales.
VASs have been thoroughly investigated concerning their validity, especially with a mobile application more recently [21][22][23][24]35 and the EAACI recommended it as a secondary outcome in AIT RCTs. 13 They may also be particularly suitable in children. 36 But VAS rating is clearly subjective 13 and does not assess the use of rescue medication. In a recent study to evaluate correlations of a VAS referring to work impairment by allergic rhinitis, overall impairment VAS was implemented into the symptom score calculation of a modified CSMS. 35 In the present study, the CSMS was used as recommended by the EAACI in its 2014 position paper. 13 It was also used in recent studies on ultrashort-course booster SCIT 37 and SLIT, 38   including the different size of the groups, must also be borne in mind, when looking at the comparisons of the outcome parameters. On the other hand, however, this daily practice routine data generated by our investigation show correlations between the CSMS and validated questionnaires. The EAACI emphasized the need for CSMS validation to be carried out in multicentre, multinational trials. 13 In that sense, although not being multinational, another strength of our studies was their multicentre design, covering different areas of Germany, with three different allergy groups and two therapy modes. However, comprehensive validation of the CSMS should be attempted in multinational, well powered phase III studies, as appealed for. 13,15 We think, our results essentially contribute to discussions, supporting the view that the CSMS is a valuable instrument to be used as clinical endpoint in ARC.